Concerns about global nuclear war, less likely than in the past, have been replaced by the real potential of a terrorist strike using radiological weapons. Significant quantities of nuclear material are missing around the world and these materials could possibility enter the black market where they would be acquired by terrorists. Thus, the threat of such attacks has grown in recent years, with the increased activity of global terrorist organizations and a rise in illicit trafficking of radioactive materials. Unfortunately, very few medical products exist to counter the variety of acute and long-term toxicities that can result from nuclear or radiological attacks. Therefore, a variety of different products and medical approaches are needed to protect and treat such a population. There remains a great need to expand the medical options available to prevent or treat radiation-induced injury. We have formed a consortium termed Radiation Countermeasures Centers of Research Excellence (RadCCORE) to collectively and collaboratively increase possible agents to detect, mitigate and treat those people exposed to deterministic doses of radiation (www.radccore.org/). Leading scientists in the area of radiation biology, health physics, stem cell biology/transplantation and immunology have come together to form one of the most comprehensive, inclusive, inter-institutional, and interdisciplinary Center for Medical Countermeasures Against Radiation (CMCR). RadCCORE (www.radccore.org) is a network of academic medical centers: Duke University, University of North Carolina, Wake Forest University and University of Arkansas for Medical Sciences and will consist of seven research projects and five support cores. A major benefit of this group of investigators has been long-term dedication and strength of the individuals in the areas of normal tissue injury, radiation biology, physics, training and education. Over the past five years, it has further evolved into a highly collaborative and interactive group of investigators. This network has addressed broad areas of research, ranging from methods to precisely measure external and internal radiation doses post-exposure to the development of new therapeutic products to prevent short- and long-term toxicities. RELEVANCE: This multi-project program will develop medical treatments for people exposed to radiation. PROJECT 2: Title: - A Molecular Signature of Radiation Injury Project Leader: Chute, J PROJECT 2 DESCRIPTION (provided by applicant): In a radiological or nuclear disaster in a populated city, tens of thousands of people could be exposed to life threatening levels of ionizing radiation. Rapid triage of affected individuals will be essential for an effective health care response to such an event. Unfortunately, there is no single accurate and practical test available to determine the level of radiation exposure that a person has received. Clinical measurements are non specific and refined assays for chromosomal aberrations require several days for completion. We hypothesized that genome-wide analysis of expression changes in the peripheral blood (PB) could predict radiation status and distinguish dose levels In irradiated Individuals. Subsequently, we succeeded in developing PB signatures of radiation injury that could predict the radiation status and radiation dose level in mice with 96% accuracy. In parallel, we demonstrated that a PB signature of human radiation exposure developed from patients undergoing total body irradiation was 97% accurate at predicting the radiation status of healthy people, non-irradiated patients and irradiated patients. However, it remains to be seen whether PB signatures of total body irradiation can distinguish individuals who receive heterogeneous radiation exposure, a group that could be numerous in a mass casualty event. We also have not explored the biological significance of the pathways altered by radiation; such pathways could provide the key basis for the development of therapeutics to mitigate radiation injury. We will: 1) Determine if PB signatures of partial body irradiation can be developed as distinct from PB signatures of total body irradiation, 2) Apply high throughput computational methods to identify gene targets and pathways that are altered in hematopoietic cells in response to radiation injury and 3) Test available drugs which modulate pathways altered by radiation as candidate mitigators of radiation injury to the hematopoietic system in a validated radiation model. Our broad objective is to refine the PB signature of radiation injury to encompass those with a heterogeneous exposure and to identify signaling pathways in hematopoietic cells that are responsive to radiation injury as a means to develop pathway specific drugs as mitigators of radiation injury. RELEVANCE: In the event of a terrorist-mediated radiological or improvised nuclear detonation, tens of thousands of people may be exposed to life threatening levels of ionizing radiation. We have developed a peripheral blood test for radiation exposure based on genetic features in the blood. We propose to improve this test by testing it against partially irradiated animals and we propose to utilize the genetic information within the test results to develop drugs to treat radiation injury and minimize the damage it causes to the blood system.